Generalized vitiligo is the most common pigmentation disorder, autoimmune death of melanocytes resulting in white patches of skin and hair, and patients are at high risk of other autoimmune diseases such as thyroid disease, adult type 1 diabetes, rheumatoid arthritis, lupus, and others. Generalized vitiligo is a "complex trait", involving both multiple genes and environmental triggers. The parent grant, AR0056292, VitGene International Consortium to Identify Susceptibility Genes for Generalized Vitiligo, funds an international consortium genomewide association study (GWAS) aimed at discovering genes that control susceptibility to generalized vitiligo. This Competitive Revision, submitted in response to FRA NOT-OD-09-079, "NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications", expands the scope of the parent grant, still in its first year, by adding the Aim of immediate detailed re-sequencing and follow-up association studies of a generalized vitiligo susceptibility gene we have already discovered, NALP1 (NLRP1), with the goal of discovering specific DNA sequence variations that cause disease. The long-term goal of these studies is to improve understanding of disease pathogenesis to facilitate developing novel treatments for vitiligo and perhaps other autoimmune diseases. This Competitive Revision project will enable hiring of additional staff and increasing hours of current part-time laboratory staff. NLRP1 encodes NALP1 (NACHT-LRR protein 1), a key regulator of the innate immune system that is likely involved in initiation of the autoimmune process. In this Competitive Revision, we propose to carry out high-throughput DNA sequence analysis of NLRP1 in year 1, re-sequencing ~175 kb across the NLRP1 region (chr17:5,340,000-5,515,000;Build 36.1) in 815 individuals, comprising the same 114 USA/UK CEU multiplex vitiligo families and the same Romanian CEU case-control cohort in which we previously identified and subsequently confirmed genetic association with NLRP1 SNPs, respectively. Subsequently, in years 1 and 2, we will carry out family-based and case-control genetic association analyses of generalized vitiligo and NLRP1 variants identified by re-sequencing. This will first be done in the 114 CEU multiplex vitiligo families and Romanian CEU case-control cohort that were sequenced, so as to identify those variants that most likely represent disease-causal variants. These specific variants will subsequently be independently tested for association with generalized vitiligo in 1500 unrelated CEU cases and 1300 CEU controls collected in the context of the generalized vitiligo GWAS supported by the parent grant, 1R01AR056292. Together, these studies will identify disease-causal variants in NLRP1 that can then be followed up by functional analyses. PUBLIC HEALTH RELEVANCE: Generalized vitiligo is the most common pigmentation disorder, autoimmune death of melanocytes resulting in white patches of skin and hair, and patients are at high risk of other autoimmune diseases such as thyroid disease, adult type 1 diabetes, rheumatoid arthritis, lupus, and others. Generalized vitiligo involves both genes and environmental triggers. The parent grant, AR0056292, VitGene International Consortium to Identify Susceptibility Genes for Generalized Vitiligo, funds an international consortium genome-wide association study (GWAS) aimed at discovering genes that control susceptibility to generalized vitiligo. This Competitive Revision expands the scope of this grant by adding the Aim of detailed studies of a generalized vitiligo susceptibility gene we have already discovered, NLRP1, with the goal of discovering specific DNA sequence variations that cause disease. The long-term goal of these studies is improve understanding of disease pathogenesis to facilitate developing novel treatments for vitiligo and perhaps other autoimmune diseases.